Sachio Kawai

Histological evaluation of coronary plaque in patients with variant angina: relationship between vasospasm and neointimal hyperplasia in primary coronary lesions

OBJECTIVES This study was designed to determine whether coronary vasospasm in patients with variant angina pectoris (VAP) may produce focal organic lesions at the site of vasospasm that would contribute to disease progression. BACKGROUND Recent clinical angiographic and experimental studies have demonstrated the potential role of vasospasm in the worsening of organic coronary stenosis. METHODS We studied histologically the coronary plaques obtained at atherectomy in 202 patients with moderate to severe coronary stenosis. This population included 22 patients with VAP, 100 patients with chronic stable angina and 80 patients with restenosis following angioplasty or atherectomy. Diagnosis of VAP was based on both the clinical feature of angina at rest associated with ST elevation and a positive response to acetylcholine provocation test. RESULTS The most common histological appearance in 92% of patients with stable angina was hypocellular fibroatheromatous plaques, whereas neointimal hyperplasia was the characteristic feature of the plaque observed in 90% of patients with restenosis. The coronary specimens at the site of spasm in 15 of the 22 patients (68%) with VAP demonstrated intimal injuries such as neointimal hyperplasia (15), thrombus formation (2), and intimal hemorrhage (3). Neointimal hyperplasia was significantly more common in the patients with VAP as compared with those with stable angina (68% vs. 8%; p < 0.0001). A rapid progression of organic stenosis within three years was angiographically found in 5 of the 22 patients with variant angina. In all five cases, neointimal hyperplasia was the main contributor to the worsening of the organic lesion at the site of spasm. These histological findings in patients with VAP extremely resembled those in restenosis. Except for vasospasm, no factors significantly predicted the presence of neointimal formations in primary coronary lesions. CONCLUSIONS Coronary vasospasm may provoke vascular injury that leads to the formation of neointima in VAP patients similar to that seen with restenosis. Coronary spasm may thus play a key role in the rapid coronary stenosis progression in certain patients with VAP.

Dilated cardiomyopathy‐associated BAG3 mutations impair Z‐disc assembly and enhance sensitivity to apoptosis in cardiomyocytes

Dilated cardiomyopathy (DCM) is characterized by dilation of left ventricular cavity with systolic dysfunction. Clinical symptom of DCM is heart failure, often associated with cardiac sudden death. About 20–35% of DCM patients have apparent family histories and it has been revealed that mutations in genes for sarcomere proteins cause DCM. However, the disease‐causing mutations can be found only in about 17% of Japanese patients with familial DCM. Bcl‐2‐associated athanogene 3 (BAG3) is a co‐chaperone protein with antiapoptotic function, which localizes at Z‐disc in the striated muscles. Recently, BAG3 gene mutations in DCM patients were reported, but the functional abnormalities caused by the mutations are not fully unraveled. In this study, we analyzed 72 Japanese familial DCM patients for mutations in BAG3 and found two mutations, p.Arg218Trp and p.Leu462Pro, in two cases of adult‐onset DCM without skeletal myopathy, which were absent from 400 control subjects. Functional studies at the cellular level revealed that the DCM‐associated BAG3 mutations impaired the Z‐disc assembly and increased the sensitivities to stress‐induced apoptosis. These observations suggested that BAG3 mutations present in 2.8% of Japanese familial DCM patients caused DCM possibly by interfering with Z‐disc assembly and inducing apoptotic cell death under the metabolic stress. 32:1481–1491, 2011. ©2011 Wiley Periodicals, Inc.

Effect of probucol on smooth muscle cell proliferation and dedifferentiation after vascular injury in rabbits : Possible role of PDGF

We previously reported a clinical study in which probucol reduced the restenosis rate. The mechanism of this effect is unclear. Restenosis is characterized by neointimal hyperplasia caused by proliferation of smooth muscle cells (SMCs), which increases the expression of Platelet-derived growth factor (PDGF)-A and SMemb. SMemb, a non–muscle-type myosin heavy chain most predominantly expressed in embryonic smooth muscle, can be used as a good molecular marker for dedifferentiated SMC. The aim of this study was to analyze the effect of probucol on neointimal proliferation and the level of expression of PDGF-A and SMemb after balloon injury in rabbits. Probucol was given orally 1.3 g/d from 2 weeks prior to carotid balloon injury to the time of killing (2 or 4 weeks after balloon injury). Intimal area was determined histologically using a computerized morphometry program. For quantification of SMC proliferation, alpha-actin–positive cells and proliferating cell nuclear antigen (PCNA)-labeled cells were counted. The expression of PDGF-A and SMemb mRNA was analyzed by the RNase protection assay. SMemb expression was also examined by immunohistochemistry. Probucol remarkably decreased intimal area by 70% and the number of SMC and PCNA-labeled cells in the intima. The expression of PDGF-A mRNA was significantly increased after balloon injury in untreated rabbits, whereas it was markedly suppressed with probucol treatment. The expression of SMemb was significantly increased in injured arteries at mRNA and protein levels. However, probucol did not suppress SMemb expression. Probucol is effective in preventing SMC proliferation, which is possibly due to a decrease in the expression of PDGF.

Apoptosis as a Possible Cause of Wall Thinning in End-Stage Hypertrophic Cardiomyopathy

A 15-year-old boy with hypertrophic cardiomyopathy died of congestive heart failure with progressive left ventricular wall thinning with poor systolic function. Microscopic examination revealed patchy fibrosis in the ventricular myocardium with wall thinning, and immunohistochemical evaluation of apoptosis showed apoptotic cells and bodies in the destroyed myocytes along the border between the fibrotic area and myofibril.

Expression of Costimulatory Molecules B7–1, B7–2, and CD40 in the Heart of Patients With Acute Myocarditis and Dilated Cardiomyopathy

BACKGROUND In patients with acute myocarditis and dilated cardiomyopathy (DCM), we previously reported that antigen-specific T cells infiltrate the heart and play an important role in the myocardial damage involved. For antigen-specific T-cell activation to occur, it is necessary for T cells to receive a costimulatory signal provided by costimulatory molecules expressed on antigen-presenting cells (APCs) as well as the main signal provided by binding of T-cell receptors to the antigen. METHODS AND RESULTS To investigate the roles of the costimulatory molecules B7-1, B7-2, and CD40 in the development of acute myocarditis and DCM, we analyzed the expression of these antigens in the myocardial tissues of patients with acute myocarditis and DCM. We also examined the expression of a cytolytic factor, perforin, in the infiltrating cytotoxic T lymphocytes (CTLs) and natural killer (NK) cells, because both killer lymphocytes are thought to damage B7-1-expressing APCs. We found that B7-1, B7-2, and CD40 were moderately to strongly expressed in the cardiac myocytes of patients with acute myocarditis. Weak to moderate expression of these antigens was also found in the cardiac myocytes of patients with DCM. There was infiltration of perforin-expressing CTLs and NK cells in the myocardial tissues of patients with acute myocarditis and DCM. CONCLUSIONS Our findings strongly suggest that expression of B7-1, B7-2, and CD40 antigens on cardiac myocytes may make them APCs for CTLs and NK cells and that they may play an important role in the direct myocardial damage by these killer cells in acute myocarditis and DCM.

Relationship between exercise tolerance and muscle strength following cardiac rehabilitation: Comparison of patients after cardiac surgery and patients with myocardial infarction

BACKGROUND AND PURPOSE Previous studies have demonstrated that cardiac rehabilitation (CR) improves exercise tolerance and muscle strength in patients with myocardial infarction (MI) and in patients after cardiac surgery. However, the association between exercise tolerance and muscular strength following CR and the comparison of relationships among various disease categories has not been fully examined. The purpose of the present study was to assess the relationship between exercise tolerance and muscle strength following CR in patients after cardiac surgery and patients with MI. METHODS AND RESULTS One hundred and four patients who participated in CR for 6 months were enrolled [post-cardiac valve surgery (VALVE), n=28; post-coronary artery bypass grafting (CABG), n=42; post-acute MI, n=34]. The exercise tolerance, thigh/calf circumferences, and muscle strength were measured before and after CR. At the baseline, the thigh circumference was significantly smaller in the VALVE group than in the MI group. There were significant positive correlations between peak VO(2) and muscle torques of the lower muscles in all groups. After 6 months, peak VO(2) and muscle torque were significantly increased in all groups (p<0.001). A positive significant correlation between percent increases in peak VO(2) and muscular strength was observed in the VALVE group (r=0.51, p<0.01), but not in the other groups. In addition, the changes in peak VO(2) and calf circumference after CR were significantly higher in the VALVE group than in the MI group. CONCLUSIONS These data suggest that exercise intolerance in patients after heart valve surgery may in part depend on decreased muscular strength. Further studies are needed to assess whether the strategy of increasing muscular strength of lower limb by programmed resistance training could be effective for improving exercise intolerance in patients after heart valve surgery and symptomatic patients with heart failure.

Effects of cardiac rehabilitation in patients with metabolic syndrome after coronary artery bypass grafting

BACKGROUND Cardiac rehabilitation (CR) has numerous beneficial effects, including the modification of coronary risk factors and improvement of the prognosis, in patients with coronary artery disease (CAD). Limited data are available regarding the effects of CR on the physical status and risk factors in patients with metabolic syndrome (MetS) after coronary artery bypass grafting (CABG). METHODS AND RESULTS We enrolled 32 patients with MetS after CABG, who participated in a supervised CR program for 6 months. Metabolic parameters, blood chemistry, exercise tolerance, and muscle strength of the thigh were measured before and after CR. After CR: (1) the body mass index, waist circumference, and fat weight significantly decreased; (2) peak V O(2) and anaerobic threshold were significantly increased; (3) isokinetic peak torques of knee extensor and flexor muscles significantly increased; (4) metabolic scoring defined by the number of the modified Adult Treatment Panel criteria of the US National Cholesterol Education Program was significantly improved; (5) serum concentration of high-sensitivity C-reactive protein also significantly decreased. CONCLUSIONS These results suggest that CR might be useful for patients with MetS after CABG.

Corticosteroid therapy for ventricular tachycardia in children with silent lymphocytic myocarditis

OBJECTIVE The objective of our study was to describe the efficacy of corticosteroids for ventricular tachycardia in four children with structurally normal hearts in whom endomyocardial biopsy revealed histologic changes of lymphocytic myocarditis. PATIENTS The four patients had unexplained ventricular tachycardia. Three dysrhythmias were sustained, and one was inducible by exercise. Patient ages ranged from 4 months to 12 years. Three of the four patients had no symptoms. In two of them, ventricular tachycardia was identified by mass screening for heart disease. Two patients received oral steroids and two received pulse steroid therapy. RESULTS In all four patients, significant underlying diseases were not found by noninvasive evaluation. Right ventricular endomyocardial biopsy revealed abnormal histologic findings of chronic lymphocytic myocarditis in all patients. Steroid therapy was effective in all four patients, two of whom received methylprednisolone pulse therapy. CONCLUSIONS We conclude that unexplained ventricular tachycardia may be the only manifestation of clinically silent myocarditis. Steroid therapy should therefore be considered if conventional antiarrhythmic medication is not effective and histologic findings confirm the presence of lymphocytic myocarditis.

Expression of tumor necrosis factor ligand superfamily costimulatory molecules CD27L, CD30L, OX40L and 4-1BBL in the heart of patients with acute myocarditis and dilated cardiomyopathy

BACKGROUND T-cell-mediated myocardial damage is known to be involved in acute myocarditis and dilated cardiomyopathy. Recently, we found that tumor necrosis factor (TNF) ligand superfamily costimulatory molecules, especially 4-1BBL, played an important role in the myocardial damage of murine acute viral myocarditis. METHODS AND RESULTS To investigate the roles for CD27L, CD30L, OX40L and 4-1BBL, which belong to TNF ligand superfamily, in the development of acute myocarditis and dilated cardiomyopathy, we analyzed the expression of these antigens in the myocardial tissues of patients with acute myocarditis and dilated cardiomyopathy. We also examined expression of the receptors for these molecules, CD27, CD30, OX40 and 4-1BB, which belong to TNF receptor superfamily, on the infiltrating cells. Strong expression of CD27L, CD30L and 4-1BBL and weak to moderate expression of OX40L was found in the cardiac myocytes of patients with acute myocarditis. Moderate expression of CD27L, CD30L and 4-1BBL and weak expression of OX40L was found on the cardiac myocytes of patients with dilated cardiomyopathy. Most of the infiltrating cells expressed CD27, CD30 and 4-1BB and a part of the infiltrating cells expressed OX40. CONCLUSIONS Our findings suggest that expression of TNF ligand superfamily costimulatory molecules on cardiac myocytes may play a role in the cell-mediated myocardial damage in patients with acute myocarditis and dilated cardiomyopathy as in murine viral myocarditis.

Three-dimensional distribution of myocardial fibrosis in the new J-2-N cardiomyopathic hamster: Comparison with electrocardiographic findings

SummaryUsing the new J-2-N strain of cardiomyopathic hamster obtained by cross-breeding Bio 14.6 and Golden hamsters, we investigated the threedimensional distribution of ventricular myocardal fibrosis and compared it with electrocardiographic (ECG) changes. Twelve-lead ECG recordings were made by our own method. The hearts were cut into serial sections and subjected to light microscopic examination. The distribution, density, and volume of myocardial interstitial fibrosis and replacement fibrosis due to myocardial degeneration (F%) were visualized three-dimensionally using the TRI system (TRI; Three-Dimensional Reconstruction Image; Ratoc System Engineering, Tokyo, Japan). Thirty-two J-2-N hamsters were divided into two groups; one group comprised 17 animals with normal hearts and normal ECG findings similar to those of Golden hamsters, and the other group of 15 hamsters had dilated hearts and abnormal ECG findings. In the normal hearts, the F% values for the right ventricle, left ventricle, and ventricular septum were 6.4 ± 0.94, 6.5 ± 0.95, and 6.5 ± 0.98 (mean ± SD), respectively. The dilated hearts showed marked fibrosis, which was distributed mainly in the middle layer of the left ventricle and the ventricular septum. The corresponding F% values for the hamsters with cardiac enlargement were 19 ± 2.6, 19 ± 1.8, and 22 ± 3.2 (mean ± SD), respectively. Replacement of myocytes by fibrosis seemed to correspond to abnormal Q waves in the anterior chest leads and left axis deviation of the QRS complex.